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March 1998

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275

Advanced Intramolecular DielsAlder Study Toward the Synthesis of ()-Morphine: Structure Correction of a Previously Reported DielsAlder Product
Gabor Butora, Andrew G. Gum, Tomas Hudlicky,* Khalil A. Abboud
Department of Chemistry, University of Florida, Gainesville, FL 32611, U.S.A. Fax +1(352)8461203; E-mail: hudlicky@chem.ufl.edu Received 21 May 1997; revised 10 August 1997 Abstract: A tricyclic ring system 18 containing all 5 chiral centers of the natural ()-morphine skeleton has been synthesized in 9 steps. cis-Dienediol 11 was produced by a batch microbial dihydroxylation of (2-azidoethyl)benzene with the E. coli strain JM109(pDTG601). The key step in the synthesis was a thermal [4+2] intramolecular DielsAlder cycloaddition of triene 16 which afforded the tricyclic adduct 17 in 62% yield. After deprotection, the absolute stereochemistry of the alcohol 18 was determined by X-ray crystallographic analysis. The previously reported Diels Alder adduct 4a was deprotected and the absolute stereochemistry of the free alcohol was assigned by X-ray crystallography to have the structure 4c. This finding therefore constitutes the correction of the structure for 4a. Key words: chemoenzymatic synthesis, ()-morphine, intramolecular DielsAlder reaction, X-ray structure proof

Morphine (7), a potent analgesic and arguably the oldest drug in recorded history, has long been a challenging target for synthetic chemists. In spite of the previously reported 17 total or formal syntheses of morphine,117 a truly practical synthesis, which would rival the economy of isolation from natural opium, continues to elude the synthetic community. Although none of the total or formal syntheses of morphine relied on a [4+2] cycloaddition as the pivotal step, several successful attempts at morphinan syntheses utilizing intramolecular DielsAlder methodology have been published.1822 In 1992, we published a model study23 that employed a DielsAlder cyclization or a DielsAlder and Cope rearrangement sequence to obtain tricycles 4a and 6 respectively (Scheme 1). The stereochemistry of 4a and 6 was deduced from NOE correlations, but the two structures have not been converted to a common intermediate for unambiguous comparison. In this paper, we report an advanced DielsAlder study and concomitant correction of the structure 4a to that of 4b via its free alcohol 4c. On the assumption that the tricycle 4a was produced stereoselectively via the endo transition state (Scheme 1), we turned to the advanced model study in which a leaving group at the incipient C9 of morphine 7 would be displaced by a nucleophilic nitrogen at C16 to form the bridged product 8 (Figure). Before committing to the halide 9b or tosylate 9c, we set out to synthesize model compound 9a by analogous DielsAlder methodology. The methyl-substituted diene provided the simplest model for establishing the stereochemical outcome of the cycloaddition of a terminally functionalized diene ether. Whole cell biooxidation of (2-azidoethyl)benzene (10b), easily synthesized from commercially available (2-bromoethyl)benzene (10a), readily afforded cis-dienedio] 11 stereospecifically and in good yield of approximately 6 g/ L24 (Scheme 2). Reduction of the less substituted olefin with diimide (generated from potassium azodicarboxy-

Scheme 1 a: (i) potassium azodicarboxylate (PAD), HOAc, MeOH; (ii) THS-Cl, imidazole, DMF; (iii) NaH, sorbyl bromide, THF. b: (i) THS-Cl, imidazole, DMF; (ii) NaH, sorbyl bromide, THF. c: toluene, sealed tube. 210C, 24 h. d: (i) CCl4, reflux, 7 h; (ii) Bu4NF3 H2O, THF, r.t., 24 h; (iii) PCC, CH2Cl2, r.t., 24 h. e: HF/MeCN (5:95), 12 h. f: (i) xylenes, sealed tube, 250C; (ii) NaBH4, CeCl37 H2O, MeOH, r.t., 15 min.

Figure. Retrosynthetic Analysis

late) afforded diol 12. Alternatively, diol 12 was obtained in a more laborious procedure by microbial dihydroxylation of (2-bromoethyl)benzene (10a) (10 g/L),25 followed by diimide reduction, and protection as the acetonide. Displacement of the bromide with sodium azide followed by acetonide cleavage afforded free diol 12.24 Selective protection of the homoallylic hydroxy group yielded silyl ether 13. Alkylation of the allylic oxygen upon exposure of its sodium alkoxide to sorbyl bromide26 gave triene 14. The azide was reduced to amine 15 and converted to acet-

276

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SYNTHESIS

amide 16. The resulting triene 16 was cyclized under conditions similar to those by which 4a was prepared23 to afford the cycloadduct 17 as a single stereoisomer in 62% yield. Since an unambiguous assignment of the absolute stereochemistry by spectroscopy was not possible, a single crystal of the alcohol 18, obtained by deprotection of tricycle 17, was grown. X-ray crystallographic analysis confirmed the stereochemistry of the cycloadduct 18 as shown27 and indicated that the [4+2] cycloaddition proceeded via an exo transition state.

available.24 For possible endo transition states, the placement of leaving groups and nucleophiles will be switched between C9 and C16. Finally, the use of E,Z-dienes equipped with terminal leaving groups (Cl, OTs, etc.) would provide additional flexibility in controlling the stereochemistry for the nucleophilic displacement and construction of the bridge. The preparation of compounds of type 9b via cycloadditions of E,Z-halodienes is currently under way and will be reported in due course.
All non-hydrolytic reactions were performed in solvents either dried according to standard procedures or purchased from Aldrich. Analytical TLC was performed on silica gel 60F-254 (Whatman). Flash chromatograaphy was performed on Fisher silica gel (grade 60, 200 425 mesh). 1H NMR spectra were recorded on a Varian VXR-300 and 13 C multiplicities were determined by APT experiments. MS were recorded on a Finnigan Mat 95 Q mass spectrometer. IR spectra were obtained on a Perkin Elmer 1600 Series instrument. Optical rotations were measured on a Perkin Elmer 341 polarimeter. Mps were obtained on a Thomas Hoover Uni-melt apparatus. (2aS,5R,5aS,8S,8aR,8bS)-5,8b-Dimethyl-2a,5,5a,6,7,8,8a,8b-octahydro-2H-benzo[cd]isobenzofuran-8-ol (4c): To a solution of tricyclic silyl ether 4b (74 mg, 0.24 mmol) in MeCN (9.5 mL) was added 48% aq HF (0.5 mL). The reaction mixture was stirred for 12 h at r.t. Water (40 mL) was added, the aqueous phase was neutralized with 10% NaOH and extracted with Et2O (3 25 mL). The combined organic phases were washed with brine and dried (MgSO4). After concentration by rotary evaporation, the crude product was purified by flash column chromatography (4:1 hexanes/ EtOAc) to afford the tricyclic alcohol 4c (32 mg, 73%) as a colorless, viscous oil which crystallized from CDCl3 by slow evaporation to obtain single crystals for X-ray analysis; Rf = 0.20 (4:1 hexanes/EtOAc). IR (CHCl3): n = 3420, 3020, 2960, 2930, 2870, 1210 cm1. 1 H NMR (300 MHz, CDCl3): d = 5.63 (dt, J = 9.5, 2.2 Hz, 1H), 5.56 (dt, J = 9.5, 2.2 Hz, 1H), 4.12 (t, J = 7.6 Hz, 1H), 3.90 (m, 1H), 3.64 (m, 2H), 3.02 (m, 1H), 2.51 (s, 1H), 1.90 (m, 2H), 1.62 (m, 1H), 1.38 (m, 3H), 1.12 (d, J = 7.6 Hz, 3H), 0.88 (s, 3H). 13 C NMR (75 MHz, CDCl3): d = 135.0 (CH), 122.3 (CH), 84.2 (CH), 69.6 (CH2), 66.4 (CH), 47.7 (CH), 42.9 (CH2), 39.6 (CH3), 37.3 (CH3), 28.5 (CH2), 23.2 (CH), 23.= (CH), 22.7 (CH2). HRMS: 209.1504 (C13H20O2+H) requires 209.1541. (1S,2R)-3-(2-Azidoethyl)cyclohex-3-ene-1,2-diol (12): To a solution of azidodienediol 11 (~35 g, 0.19 mol) in MeOH (300 mL) was added potassium azodicarboxylate (PAD, 85 g, 0.44 mol). The suspension was cooled to 0 C, and a mixture of HOAc (50 mL) and MeOH (100 mL) was added dropwise over 2 h. The solution was allowed to warm to r.t. and continued stirring for 14 h. Additional HOAc (10 mL) was added to decompose any excess PAD, and the mixture was concentrated by rotary evaporation. Water (150 mL) was added and the crude product was extracted into CH2Cl2 (5 50 mL). The combined organic layers were washed with brine, dried (MgSO4), and concentrated under reduced pressure. The remaining solid was recrystallized (CH2Cl2/hexanes) to afford diol 12 (25 g, 72%) as a white crystalline material; mp 5455 C; Rf = 0.13 (1:1, 29 hexane/EtOAc); [a]D 98.5 (c = 1.0, CHCl3). Anal. Found: C, 52.47; H, 7.09; N, 22.78. C8H13O2N3 requires: C, 52.43; H, 7.16; N, 22.94. IR (KBr): n = 3280, 2940, 2095, 1260, 1080 cm1. 1 H NMR (300 MHz, CDCl3): d = 5.66 (bs, 1H), 3.99 (d, J = 3.4 Hz, 1H), 3.75 (m, 1H), 3.40 (t, J = 7 Hz, 2H), 2.96 (s, 2H), 2.40 (m, 2H), 2.16 (m, 1H), 2.08 (m, 1H), 1.70 (m, 2H). 13 C NMR (75 MHz, CDCl3): d = 133.9 (C), 128.1 (CH), 69.5 (CH), 68.6 (CH), 50.1 (CH2), 34.0 (CH2), 25.1 (CH2), 23.9 (CH2). MS (EI): m/z (%) = 184 (M+, 8), 138 (42), 120 (100). HRMS: 184.1153, (C8H13O2N3+H) requires 184.1086.

Scheme 2 a: NaN3, DMF. b: E. coli JM109(pDTG601). c: PAD, HOAc, MeOH, 0Cr.t., 14 h. d: THSCl, imidazole, DMF, 0C, 13 h. e: NaH, sorbyl bromide, THF, 0 Cr.t., 14 h. f: PPh3. 0.4% H2O/THF, 45 C 18 h. g: Ac2O, pyridine, r.t., 2 h. h: toluene, sealed tube, 230C, 20 h. i: HF/MeCN (5:95), r.t., 3.5 h.

On the basis of this observation, we reinvestigated the stereochemical assignment of the reported endo cycloadduct 4a by X-ray crystallography of its free alcohol and confirmed this structure as 4c,28 therefore proving that the intramolecular DielsAlder reaction proceeded in an exo fashion to afford both 18 and 4c. This result serves as a formal structure correction of cycloadduct 4a. The combination of enzymatic chemistry and a stereospecific intramolecular DielsAlder reaction allowed for the efficient synthesis of tricycle 18, which contains all of the stereocenters of natural ()-morphine in the correct absolute configuration. It is noteworthy that the intramolecular DielsAlder cyclization led to the correct stereochemistry of both C14 and C9 of morphine, a feat not simultaneously attained by most of the previously reported strategies. In light of the stereochemical outcome of the DielsAlder reaction, it is clear that our next strategy must focus on a flexible approach to accommodate the exo versus endo options in the [4+2] cycloaddition. If the E,E-dienes continue to produce the b-C9 stereochemistry via the exo transition state in the thermal cycloaddition, then C9 will need to contain a nucleophilic nitrogen while a leaving group will be installed at C16 (see numbering in morphine 7) that is on the ethyl side chain of diols such as 11. Several such compounds (X=OH, OAc, etc.) have recently become

March 1998 (1R,6S)-2-(2-Azidoethyl)-6-(dimethylthexylsiloxy)cyclohex-2-en1-ol (13): To a cooled (0C) solution of diol 12 (122 mg, 0.67 mmol) in DMF (0.75 mL) was added imidazole (54 mg, 0.80 mmol) followed by THS-Cl (142 mg, 0.80 mmol). The mixture was stirred briefly and allowed to stand at 0 C for 13 h. Water (40 mL) was added and the aqueous layer was extracted with Et2O (3 15 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by column chromatography (9:1 hexane/EtOAc) to afford 13 (214 mg, 99%) as a colorless oil; Rf 26 = 0.49 (9:1 hexane/EtOAc); [a]D 37.0 (c = 1.2, CHCl3). Anal. Found: C, 59.11; H, 9.64; N, 12.84. C16H31O2N3Si requires: C, 59.04; H, 9.60; N, 12.91. IR (CHCl3): n = 3550, 2950, 2095, 1460, 1370, 1250, 1080 cm1. 1 H NMR (300 MHz, CDCl3): d = 5.65 (bs, 1H), 3.89 (bs, 1H), 3.81 (dt, J = 10.7, 3.9 Hz, 1H), 3.41 (m, 2H), 2.66 (d, J = 2.7 Hz, 1H), 2.42 (m, 2H), 2.17 (m, 1H), 2.02 (m, 1H), 1.77 (m, 1H), 1.63 (sept, J = 6.9 Hz, 1H), 1.55 (m, 1H), 0.89 (d, J = 6.9 Hz, 3H), 0.88 (d, J = 6.9 Hz, 3H), 0.85 (s, 6H), 0.14 (s, 3H), 0.13 (s, 3H). 13 C NMR (75 MHz, CDCl3): d = 133.7 (C), 127.6 (CH), 70.8 (CH), 68.8 (CH), 50.0 (CH2), 34.5 (CH2), 34.2 (CH), 25.3 (CH2), 24.9 (C), 24.1 (CH2), 20.3 (CH3), 20.2 (CH3), 18.6 (CH3), 18.5 (CH3), 2.4 (CH3), 3.0 (CH3). MS (EI) m/z (%) = 308 (M-H2O+, 45), 280 (100). (5S,6R)-1-(2-Azidoethyl)-5-(dimethylthexylsiloxy)-6-[(2E,4E)hexa-2,4-dienyloxy]cyclohex-1-ene (14): To a cooled (0C) suspension of 60% NaH in mineral oil (117 mg, 2.92 mmol) in THF (1 mL) was added dropwise a solution of the mono protected azide 13 (476 mg, 1.46 mmol) in THF (2 mL). The mixture stirred at 0C for 20 min. A solution of sorbyl bromide (353 mg, 2.19 mmol) in THF (1 mL) was added dropwise. The cooling bath was removed and the mixture was stirred for 14 h. Water (70 mL) was added and the crude product was extracted into Et2O (3 30 mL). The combined organic layers were washed with brine and dried (MgSO4). Removal of solvent under reduced pressure gave a crude product which was purified by repeated column chromatography (99:1 hexane/EtOAc) [note: 3 separate columns were necessary to separate the product from unreacted sorbyl bromide] to afford 14 as a pale yellow oil (344 mg, 58%); Rf = 0.61 (95:5 hexane/EtOAc); 26 [a]D 53.2 (c = 1.11, CHCl3). IR (CHCl3): n = 2950, 2870, 2095, 1460, 1380, 1250, 1100 cm1. 1 H NMR (300 MHz, CDCl3): d = 6.17 (dd, J = 14.8, 10.2 Hz, 1H), 6.05 (ddd, J = 14.7, 10.4, 1.7 Hz, 1H), 5.68 (m, 2H), 5.55 (bs, 1H), 4.46 (dd, J = 12.1, 5.8 Hz, 1H), 4.09 (dd, J = 12.1, 7.1 Hz, 1H), 3.82 (dt, J = 11.0, 3.0 Hz, 1H), 3.64 (d, J = 3.0 Hz, 1H), 3.33 (m, 2H), 2.34 (m, 2H), 2. 18 (m, 1H), 2.03 (m, 1H), 1.90 (m, 1H), 1.75 (d, J = 6.6 Hz, 3H), 1.66 (sept, J = 6.8 Hz, 1H), 1.58 (m, 1H), 0.91 (s, 3H), 0.89 (s, 3H), 0.86 (s, 3H), 0.85 (s, 3H), 0.12 (s, 6H). 13 C NMR (75 MHz, CDCl3): d = 133.5 (C), 133.0 (CH), 130.9 (CH), 129.8 (CH), 127.7 (CH), 127.3 (CH), 76.9 (CH), 73.0 (CH2), 71.9 (CH), 50.2 (CH2), 34.1 (CH2), 34.0 (CH3), 25.7 (CH2), 24.9 (C), 24.8 (CH2), 20.3 (2 x CH3), 18.6 (CH3), 18.1 (CH3), 2.6 (2 CH3). HRMS: 406.2824, (C22H39O2N3Si+H) requires 406.2889. (5S,6R)-1-(2-Aminoethyl)-5-(dimethylthexylsiloxy)-6-[(2E,4E)hexa-2,4-dienyloxy]cyclohex-1-ene (15): To a solution of azide 14 (106 mg, 0.26 mmol) in THF (10 mL) was added PPh3(102.8 mg, 0.39 mmol) and water (0.04 mL). After stirring at 45 C for 18 h, the mixture was concentrated under reduced pressure and the crude product was purified by column chromatography (EtOAc-50% saturated with NH4OH) [note: The eluent was prepared by diluting EtOAc fully saturated with NH4OH with an equal volume of 100% EtOAc] to afford the amine 15 as a pale yellow oil (65 mg, 28 66%); Rf = 0.71 (7:3: 1 EtOAc/ EtOH/NH4OH); [a]D 72.5 (c = 1.22, CHCl3). IR (CHCl3): n = 3020, 2960, 2870, 1220, 1090 cm1. 1 H NMR (300 MHz, CDCl3): d = 6.15 (dd, J = 14.9, 10.5 Hz, 1H), 6.05 (ddd, J = 14.4, 9.0, 1.5 Hz, 1H), 5.66 (m, 2H), 5.46 (s, 1H), 4.46 (dd, J = 12.5, 6.1 Hz, 1H), 4.08 (dd, J = 11.7, 6.8 Hz, 1H), 3.78 (dt, J = 11.2, 3.2 Hz, 1H), 3.58 (d, J = 2.7 Hz, 1H), 2.76 (m, 2H), 2.18 (m,

SYNTHESIS

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2H), 2.02 (m, 1H), 1.94 (m, 1H), 1.72 (d, J = 6.8 Hz, 3H), 1.66 (sept, J = 6.8 Hz, 1H), 1.57 (m, 1H), 1.38 (bs, 2H), 0.90 (s, 3H), 0.88 (s, 3H), 0.84 (s, 6H), 0.12 (s, 6H). 13 C NMR (75 MHz, CDCl3): d = 134.7 (C), 132.7 (CH), 130.9 (CH), 129.5 (CH), 128.0 (CH), 126.3 (CH), 77.3 (CH), 73.2 (CH2), 72.6 (CH), 40.4 (CH2), 39.2 (CH2), 34.0 (CH3), 25.6 (CH2), 25.0 (C), 24.9 (CH2), 20.3 (CH3), 20.2 (CH3), 18.6 (CH3), 18.5 (CH3), 2.6 (2 CH3). HRMS: 380.2977, (C22H41O2NSi+H) requires 380.2984. (5S,6R)-1-(2-Acetamidoethyl)-5-(dimethylthexylsiloxy)-6[(2E,4E)-hexa-2,4-dienyloxy]cyclohex-1-ene (16): To a solution of amine 15 (263 mg, 0.69 mmol) in pyridine (2 mL) was added Ac2O (106 mg, 1.04 mmol), and the mixture was stirred at r.t. for 2 h. The solvent was removed by rotary evaporation, and the crude product was purified by column chromatography (100% EtOAc) to afford the amide 16 (259 mg, 89%) as a colorless, viscous 28 oil; Rf = 0.69 (EtOAc fully saturated with NH4OH); [a]D 78.9 (c = 1.15, CHCl3). IR (CHCl3): n = 3450, 3020, 2980, 2900, 1660, 1520, 1220, 1050 cm1. 1 H NMR (300 MHz, CDCl3): d = 6.18 (dd, J = 14.8, 10.2 Hz, 1H), 6.03 (ddd, J = 14.8, 10.4, 1.7 Hz, 1H), 5.67 (m, 2H), 5.51 (bs, 1H), 4.52 (dd, J = 11.8, 6.0 Hz, 1H), 4.05 (dd, J = 11.8, 7.0 Hz, 1H), 3.83 (dt, J = 10.7, 3.3 Hz, 1H), 3.61 (d, J = 2.8 Hz, 1H), 3.31 (m, 2H), 2.32 (m, 1H), 2.10 (m, 3H), 1.92 (m, 1H), 1.89 (s, 3H), 1.74 (d, J = 6.9 Hz, 3H), 1.64 (sept, J = 6.9 Hz, 1H), 1.56 (m, 1H), 0.89 (s, 3H), 0,88 (s, 3H), 0.84 (s, 6H), 0.12 (s, 3H), 0.11 (s, 3H). 13 C NMR (75 MHz, CDCl3): d = 170.0 (C), 134.1 (C), 133.4 (CH), 130.8 (CH), 130.2 (CH), 127.4 (CH), 127.2 (CH), 77.9 (CH), 73.0 (CH2), 71.9 (CH), 38.7 (CH2), 34.3 (CH2), 34.0 (CH3), 25.8 (CH2), 24.9 (C), 24.7 (CH2), 23.3 (CH), 20.4 (CH3), 20.2 (CH3), 18.6 (CH3), 18.5 (CH3), 2.6 (2 CH3). MS (FAB): m/z (%) = 422 (M+H+, 4), 324 (86), 265 (98). HRMS: 422.3056, (C24H43O3NSi+H) requires 422.3090. (2aS,5R,5aS,8S,8aR,8bS)-8b-(2-Acetamidoethyl)-8-(dimethylthexylsiloxy)-5-methyl-2a,5,5a,6,7,8,8a,8b-octahydro-2H-benzo[cd]isobenzofuran (17): A solution of triene 16 (126 mg, 0.299 mmol) in toluene (15 mL) was placed in a thick-wall glass reaction tube equipped with a Teflon screw cap. The reaction mixture was degassed using 3 repeated freeze-pump-thaw cycles, lowering the reaction tubes temperature to 78 C at the start of each cycle, and sealed under argon. The reaction tube was placed in a sand bath preheated to 230 C. After 20 h, the tube was cooled in a liquid nitrogen bath, carefully opened, and the contents removed. The toluene was distilled off under reduced pressure, and the crude product was purified by column chromatography (100% EtOAc) to afford the tricycle 17 (78 mg, 62%) as a colorless oil. Crystallization from hexanes afforded colorless crystals; mp 123 26 124C; Rf = 0.21 (100% EtOAc); [a]D +11.0 (c = 1.0, CHCl3). Anal. Found: C, 67.85; H, 10.03; N, 3.24. (C24H43NO3Si) requires: C, 68.36; H, 10.28; N, 3.32. (Best result obtained after repeated analyses of recrystallized product.) IR (KBr): n = 3240, 2960, 2860, 1640, 1560, 1440, 1380, 1250, 1080 cm1. 1 H NMR (300 MHz, CDCl3): d = 5.64 (dt, J = 9.6, 2.8 Hz, 1H), 5.57 (dt, J = 9.6, 2.8 Hz, 1H), 5.44 (bs, 1H), 4.10 (dd, J = 8.8, 6.9 Hz, 1H), 3.95 (t, J = 3.6 Hz, 1H), 3.71 (d, J = 5.2 Hz, 1H), 3.54 (dd, J = 11.5, 6.9 Hz, 1H), 3.42 (m, 1H), 3.29 (m, 1H), 3.12 (m, 1H), 1.94 (s, 3H), 1.90 (m, 1H), 1.64 (m, 5H), 1.44 (m, 1H), 1.27 (m, 2H), 1.14 (d, J = 7.7 Hz, 3H), 0.87 (d, J = 6.9 Hz, 6H), 0.83 (s, 6H), 0.12 (s, 3H), 0.08 (s, 3H). 13 C NMR (75 MHz, CDCl3): d = 169.9 (C), 135.1 (CH), 123.2 (CH), 79.8 (CH), 68.6 (CH2), 68.1 (CH), 45.9 (C), 42.7 (CH), 40.0 (CH), 37.4 (CH), 35.8 (CH2), 34.0 (CH), 31.4 (CH2), 30.1 (CH2), 24.8 (C), 23.3 (CH3), 23.0 (CH3), 22.9 (CH2), 20.2 (2 CH3), 19.0 (CH3), 18.5 (CH3), 2.6 (CH3), 3.2 (CH3). MS (FAB) m/z = 422 (M+H)+. HRMS: 422.3056, (C24H43O3NSi+H) requires, 422.3090.

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Papers

SYNTHESIS (8) Rice, K. C. J. Org. Chem. 1980, 45, 3135. (9) Evans, D. A.; Mitch, C. H. Tetrahedron Lett. 1982, 23, 285. (10) Moos, W. H.; Gless, R. D.; Rapoport, H. J. J. Org. Chem. 1983, 48, 227. (11) White, J. D.; Caravatti, G.; Kline, T. B.; Edstrom, E.; Rice, K. C.; Brossi, A. Tetrahedron 1983, 39, 2393. (12) Ludwig, W.; Schfer, H. J. Angew. Chem., Int. Ed. Engl. 1986, 25, 1025. (13) Toth, J. E.; Fuchs, P. L. J. Org. Chem. 1987, 52, 473. (14) Tius, M. A.; Kerr, M. A. J. Am. Chem. Soc. 1992, 114, 5959. (15) Parker, K. A.; Fokas, D. J. Am. Chem. Soc. 1992, 114, 9688. (16) Hong, C. Y.; Kado, N.; Overman, L. E. J. Am. Chem. Soc. 1993, 115, 11028. (17) Mulzer, J.; Drner, G.; Trauner, D, Angew. Chem. 1996, 108, 3046; Angew. Chem., Int. Ed. Engl. 1996, 35, 2830. (18) Ciganek, E. J. Am. Chem. Soc., 1981, 103, 6261. (19) Handa, S.; Jones, K.; Newton, C. G.; Williams, D. J. J. Chem. Soc., Chem. Commun. 1985, 1362. (20) Kametani, T.; Suzuki, Y.; Honda, T. J. Chem. Soc., Perkin Trans. 1 1986, 1373. (21) Constanzo, M. J. Ph. D. Thesis, Temple University, 1988. (22) Wu, C. Ph. D. Thesis, Columbia University, 1990. (23) Hudlicky, T.; Boros, C. H.; Boros, E. E. Synthesis 1992, 174. (24) Hudlicky, T.; Endoma, M. A. A.; Butora, G. J. Chem. Soc., Perkin Trans. 1 1996, 2187. (25) Stabile, M. R.; Hudlicky, T.; Meisels, M. L. Tetrahedron Asymmetry 1995, 6, 537. (26) Mori, K. Tetrahedron 1974, 30, 3807. (27) X-ray data for 18: C16H25NO3, Mr = 279.37, Orthorhombic, P212121, a = 7.6014(1) , b = 10.6199(3) , c = 18.8051(6) , V = 1518.06(7) 3, Z = 4, Dcalc. = 1.222 g cm3, Mo Ka (l = 0.71073 A), T = 173 K. The structure was solved by the Direct Methods in SHELXTL5, and refined using full-matrix least squares. The non-H atoms were treated anisotropically. The hydrogen atoms were obtained from a Diffference Fourier map and refined without constraints. 282 parameters were refined in the final cycle of refinement using 2530 reflections with I > 2s(I) to yield R1 and wR2 of 3.87 and 7.41%, respectively. Refinement was done using F2. (28) X-ray data for 4c: C13H20O2, Mr = 208.29, Orthorhombic, P212121, a = 6.2053(2) , b = 1386542(1) , c = 13.8944(4) , V = 1177.25(5) 3, Z = 4, Dcalc. = 1.175 g cm3, Mo Ka (l = 0.71073 ), T = 173 K. The structure was solved by the Direct Methods in SHELXTL5, and refined using full-matrix least squares. The non-H atoms were treated anisotropically. The hydrogen atoms were obtained from a Diffference Fourier map and refined without constraints. 217 parameters were refined in the final cycle of refinement using 2236 reflections with I > 2s(I) to yield R1 and wR2 of 4.26 and 9.15%, respectively. Refinement was done using F2. Sheldrick, G. M. (1995). SHELXTL5. Siemens Analytical Instrumentation, Madison, Wisconsin, USA.

(2aS,5R,5aS,8S,8aR,8bS)-8b-(2-Acetamidoethyl)-5-methyl2a,5,5a,6,7,8,8a,8b-octahydro-2H-benzo[cd]isobenzofuran-8-ol (18): To a solution of tricycle 17 (90 mg, 0.21 mmol) in MeCN (9.5 mL) was added 45% aq HF (0.5 mL). The mixture was stirred at r.t. for 1.5 h and another portion of 45% aq HF (0.5 mL) was added. After stirring an additional 2 h, the mixture was neutralized with 10% NaOH and extracted with Et2O (3 10 mL), The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by column chromatography (95:5 EtOAc/MeOH) to obtain the alcohol 18 (24 mg, 65%) as a colorless, viscous oil. Crystallization from CDCl3 (the solution was allowed to evaporate slowly from a capped tube at r.t. over several weeks) afforded single crystals suitable for X-ray analysis; mp 186188 C; Rf 29 = 0.21 (95:5 EtOAc/MeOH); [a]D +5.75 (c = 0.4, CHCl3). Anal. Found: C, 68.59; H, 8.98, N, 5.03. (C16H25NO3) requires C, 68.79; H, 9.02; N, 5.01. IR (neat) n = 3680, 3020, 2980, 1730, 1670, 1520, 1420, 1210, 1050 cm1. 1 H NMR (300 MHz, CDCl3): d = 5.60 (bs, 1H), 5.49 (bs, 1H), 4.15 (t, J = 8.3 Hz, 1H), 3.94 (m, 1H), 3.85 (d, J = 5.6 Hz, 1H), 3.63 (dd, J = 12.0, 7.6, Hz, 1H), 3.41 (m, 1H), 3.18 (m, 2H), 2.21 (bs, 1H), 1.94 (s, 3H), 1.90 (bs, 1H), 1.68 (m, 3H), 1.43 (m, 1H), 1.26 (m, 3H), 1.15 (d, J = 7.8 Hz, 3H). 13 C NMR (75 MHz, CDCl3): d = 170.0 (C), 135.5 (CH), 122.0 (CH), 80.2 (CH), 69.2 (C), 66.5 (CH), 45.5 (C), 42.4 (CH), 40.6 (CH), 37.4 (CH), 35.8 (CH2), 31.2 (CH2), 28.3 (CH2), 23.3 (CH3), 22.9 (CH3), 22.6 (CH2). MS (CI/methane): m/z (%) = 280 (M+H+, 100), 262 (35). HRMS: 280.1959, (C16H25NO3+H) requires 280.1912. The authors wish to thank the National Science Foundation, TDC Research, Inc., and the University of Florida for funding. K.A.A. wishes to acknowledge the National Science Foundation for funding of the purchase of the X-ray equipment. (1) Gates, M.; Tschudi, G. J. Am. Chem. Soc. 1952, 74, 1109. Gates, M.; Tschudi, G. J. Am. Chem. Soc. 1954, 78, 1380. (2) Elad, D.; Ginsburg, D. J. Am. Chem. Soc. 1954, 76, 312. (3) Barton, D. H. R.; Kirby, G. W.; Steglich, W.; Thomas, G. M. Proc. Chem. Soc., London 1963, 203. (4) Morrison, G. C.; Waite, R. P.; Shavel, J. Jr. Tetrahedron Lett. 1967, 4055. Grewe, R.; Friedrichsen, W. Chem. Ber. 1967, 100, 1550. (5) Kametani, T.; Ihara, M.; Fukumoto, K.; Yagi, H. J. Chem. Soc., Chem. Commun. 1969, 2030. (6) Schwartz, M. A.; Mami, I. S. J. Am. Chem. Soc. 1975, 97, 1239. Schwartz, M. A.; Pham, P. T. K. J. Org. Chem. 1988, 53, 2318. (7) Lie, T. S.; Maat, L.; Beyerman, H. C. Recl. Trav. Chim. PaysBas 1979, 98, 419.